The Veterans Aging Cohort Study (VACS) is an 8 site, continuing observational study of 3216 veterans with and 3163 veterans without HIV. Our long-range goal is to design and implement interventions to improve survival and quality of life for HIV positive individuals. Because most individuals with HIV use alcohol, we are focused on understanding its modifiable role in determining adverse medical outcomes. We have fulfilled our original aims. Specifically, we have shown that alcohol use has a temporal and dose-response association with adverse medical outcomes including adherence, viral load, symptoms, and comorbid disease. We have shown that alcohol related biomarkers predict decreased survival, and that even moderate alcohol use shortens survival using computer simulation. We have explored patient and provider attitudes and found that HIV-positive veterans and their physicians view alcohol as a secondary problem compared to drug use. Further, HIV providers are often unaware of hazardous consumption and are less likely to counsel patients to stop or curtail alcohol than are general medical providers. Two hypotheses that require further exploration concern the association between alcohol and treatment toxicity and the direct association of alcohol with survival. These require more intermediate observations and longer term follow up. Further, as a maturing cohort study with in-depth clinical data supplemented with detailed alcohol data and blood samples on 3216 HIV-positive veterans with and 3163 HIV-negative controls, VACS is uniquely positioned to support and inform intervention research. With more intermediate observations and longer follow-up, VACS can provide critical information, concerning quantity/frequency of alcohol use over time and its association with: biomarkers of alcohol and mitochondrial-related injury;treatment toxicity;and survival, across HIV status. Of particular importance will be the differentiation between effects of alcohol that are related to past and current use from those related to continued use which are modifiable with intervention. Our goals for the next five years are: 1) to utilize blood specimens and alcohol data to evaluate bio- markers for alcohol and mitochondrial toxicity and develop an Index of Alcohol Related Frailty applicable to both HIV positive and HIV negative veterans, 2) to obtain longer follow-up and more intermediate observations to characterize the roles of past and current vs. continuing alcohol use in determining adverse medical outcomes and survival;and to compare and contrast these roles by HIV status 3) to use longitudinal models and computer simulation to determine the threshold of alcohol consumption associated with adverse medical outcomes and to determine whether HIV positive individuals experience adverse medical outcomes at lower quantity/frequency alcohol exposure than HIV negative controls.